Unexplained Hyperglycemia Research Articles

Insulin infusion sets associated with adverse events: strategies for improved diabetes education

IntroductionInsulin Infusion Sets (IIS) play a crucial role in ensuring the safe delivery of insulin through a Continuous Subcutaneous Insulin Infusion (CSII) for individuals with Type 1 Diabetes (T1D). Recent advancements in therapy have highlighted the need to address issues such as unexplained hyperglycemia and IIS occlusion.ObjectiveTo investigate the adverse events (AEs) associated with IIS that impact the treatment of T1D, with a specific focus on promoting effective educational practices.MethodsOne hundred and eighteen patients under treatment at the Diabetes Center Insulin Pump Ambulatory, Federal University of São Paulo responded to a semi-structured questionnaire. Over 6 months, a nurse researcher interviewed them via video calls.ResultsCatheter-related adverse events (AEs) included catheter knots, folding, and accidental traction. AEs associated with cannula use were mainly related to cannula fixation adhesive, insulin leakage, bleeding episodes, and skin problems. The cannula patch tends to detach easily in hot conditions or when used for more than 3 days, leading to local itching. Adhesive glue can cause redness and pain. Insulin leakage typically occurs after the catheter disconnects from the cannula, accidental cannula traction, or beneath the cannula patch. Bleeding has been reported inside the cannula or at the insertion site, resulting in local pain and, in some cases, obstruction of insulin flow. When accidental cannula traction occurs, it is recommended to replace the entire IIS system. In situations involving bleeding, leakage, insulin odor, or unsuccessful attempts to correct hyperglycemic episodes with a “bolus” of insulin, it is advisable to change the IIS system and evaluate appropriate techniques for handling and infusing the device. Moreover, regular inspections of the device and reservoir/cartridge are essential.ConclusionSerious AEs can occur even in cases where the occlusion alarm is not activated, leading to interruptions in insulin flow. Conversely, in less severe situations, alarm activation can occur even in the absence of insulin flow interruption. Accidental catheter traction and catheter bending are commonly encountered in everyday situations, while issues related to the cannula directly affect blood glucose levels. AEs related to the IIS cannula often involve insulin leakage into the skin, bleeding, and skin events attributed to adhesive issues with the cannula.

THU281 Real-World Survey Of Adherence To Guidelines Regarding Type 1 Diabetes And Aerobic Exercise

Abstract Disclosure: J.A. Henske: None. G. Beach: None. A. Albashaireh: None. Background: Managing hyperglycemia and hypoglycemia before, during, and after aerobic exercise remains one of the greatest challenges for those living with type 1 diabetes. Several publications offer guidelines and recommendations but it is not well established to what extent these are followed by those living with diabetes. In order to assess the implementation and awareness of these guidelines and in particular guidelines around risk of hypoglycemia and safety recommendations, we created an online survey which was posted to focused social media groups limited to adults with type 1 diabetes who run, jog, or walk for exercise. Results: The entire 96-question survey was completed by 102 adults with a mean age of 42 and a mean duration of diabetes of 20 years. The self-reported average HbA1c of respondents was 7.1%. 68% of respondents reported exercise 4 or more days per week. Average mileage was 23 miles per week. The respondents were predominantly female (69%), Caucasian (94%), and from the United States (78%). There was a high rate of technology use as 97% of respondents report using CGM and 75% are using insulin pumps. 80% reported learning about diabetes and exercise mostly from trial and error, 46% from social media, 32% from their medical team, 28% from online searches, some using multiple methods. 27% of respondents reported fear of hypoglycemia as a significant barrier to exercise and 36% reported increased glucose variability as a result of exercise. 19% of respondents reported having hypoglycemia unawareness. 3% reported never having symptoms of hypoglycemia at any glucose level, 21% feel first symptoms with BG <50mg/dL, 26% at 50-60 mg/dL, and 40% at 60-70mg/dL. Despite published guidelines, 73% reported that they exercise even if severe hypoglycemia <50mg/dL in the last 24 hours, 74% do not check for ketones even if unexplained hyperglycemia >250mg/dL prior to exercise. 11% reported exercising with ketones present in blood or urine. 10% reported developing DKA after exercise. 86% experienced the need to stop exercise due to hypoglycemia and 18% reported a severe hypoglycemic event during exercise. 49% report not wearing diabetes identification during exercise. 41% reported difficulty with overnight hypoglycemia after exercise. Conclusion: In a real-world survey of 102 individuals with relatively well-controlled type 1 diabetes (mean A1c 7.1%) who walk, run, or jog extensively for exercise (23 miles per week), hypoglycemia awareness and management is a significant concern and barrier for them. Implementation science efforts and increased awareness of current guidelines and development of an educational curriculum surrounding type 1 diabetes and exercise may prove helpful to improve outcomes. Presentation: Thursday, June 15, 2023

107-LB: Clinical Performance of Extended Mio 30 Infusion Set

Objective: Medtronic Mio™ 30 infusion set (M30IS) is a single use IS for pump users with pre-loaded inserter, a 30° insertion angle, and labeled for 3-day use. The M30IS wear duration is impacted by initial local trauma caused by insertion and sustained inflammation by cannula & insulin infusion (insulin aggregates & other impurities in the infusate), with the latter being predominant. An extended Mio™ 30 infusion set (EM30IS) was developed by improving insulin formulation stability in the fluid path. This study reports on the performance of the EM30IS in persons with T1D during an early feasibility trial (ClinicalTrials.gov: NCT05544643). Method: This is a X over study of EM30IS and M30IS on 21 subjects with type 1 diabetes. Each subject wore both sets 4-5 times each on a preferred site that was continuously infused with insulin lispro or aspart subcutaneously via a Medtronic 780G pump for 3 days (M30IS), 7 days (EM30IS) or until failure. Endpoints of safety and effectiveness (failure rate due to unexplained hyperglycemia <16%) were evaluated. Exploratory analyses related to performance and glycemic control were also evaluated. Results: The EM30IS survival rate at 6 days (70%) was comparable to M30IS survival rate at 3 days (63%). Glycemic control outcomes were equivalent (see Table 1) and there were no episodes of EM30IS-related severe hypoglycemia or DKA. Conclusion: The EM30IS was safe and its performance at 6 days was equivalent to the performance of M30IS at 3 days. Disclosure O. Cohen: Employee; Medtronic. Y. Cohen: None. S. Chattaraj: Employee; Medtronic. G. Zhang: Employee; Medtronic. E. Anselmo: Employee; Medtronic. A. Tirosh: Advisory Panel; Medtronic. Research Support; Medtronic. Speaker's Bureau; Medtronic. Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Research Support; Sanofi. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Funding Medtronic

905-P: Clinical Comparison of Infusion Sets with Angled and 90° Teflon Cannulas

Objective: Insulin pump users worldwide depend on insulin infusion sets (IISs) for predictable delivery of insulin to the subcutaneous tissue. Yet emerging data indicates that IISs are associated with many pump-related adverse events and may contribute to potentially life-threatening problem of unexplained hyperglycemia. The relative scarcity of published research on IISs to date contributed to the difficulty of IIS section and recommendation. In this cross-over clinical study, a commercial Mio30 infusion set (M30IS) with 30° Teflon cannula was put into head-to-head comparison with a commercial Quick-set infusion set (QIS) with Teflon cannula. Method: This is a cross over study of M30IS and QIS on 20 subjects with Type 1 diabetes. Each subject wore both sets for a month each on a preferred site that was continuously infused with insulin lispro or insulin aspart subcutaneously via a Medtronic 780G pump system for 3 days or until failure. The overall IIS survival rates, glycemic control outcomes (i.e., mean sensor glucose and time spent in established glucose ranges), total daily insulin delivered (TDD), and satisfaction with both IISs were determined. Result: The 20 study subjects comprised of 50% men/women, at 41.3 ± 13.7 years, with BMI 25.7 ± 4.3 and HbA1c 7.0 ± 0.8. Based on the data collected, mean wear duration for the M30IS and QIS was 3.03 and 3.20 days, respectively. The M30IS had slightly more set failures (9.9%) than the QIS (4.4%). TDD and %Time in Range were statistically identical for both M30IS and QIS. Between the two IISs, more people preferred QIS over M30IS Teflon cannula. Conclusion: Choosing between IISs with angled and 90° Teflon cannulas may be a personal preference. In terms of glycemic control, there was no statistical difference between the two IISs. Disclosure O.Cohen: Employee; Medtronic. Y.Cohen: None. S.Chattaraj: Employee; Medtronic. G.Zhang: Employee; Medtronic. E.Anselmo: Employee; Medtronic. A.Tirosh: Advisory Panel; Medtronic, Novo Nordisk, Sanofi, Eli Lilly and Company, Research Support; Medtronic, Sanofi, Speaker's Bureau; Medtronic, Novo Nordisk, Sanofi, Eli Lilly and Company. Funding Medtronic

Diagnosis and treatment of allograft rejection in islet transplantation

Islet transplantation stabilizes glycemic control in patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable method to assess rejection, and treatment protocols are absent. We aimed to characterize diagnostic features of islet allograft rejection and assess effectiveness of high-dose methylprednisolone treatment. Over a median follow-up of 61.8 months, 22% (9 of 41) of islet transplant recipients experienced 10 suspected rejection episodes (SREs). All first SREs occurred within 18 months after transplantation. Important features were unexplained hyperglycemia (all cases), unexplained C-peptide decrease (ΔC-peptide, 77.1% [−59.1% to −91.6%]; ΔC-peptide:glucose, −76.3% [−49.2% to −90.4%]), predisposing event (5 of 10 cases), and increased immunologic risk (5 of 10 cases). At 6 months post-SRE, patients who received protocolized methylprednisolone (n = 4) had significantly better islet function than untreated patients (n = 4), according to C-peptide (1.39 ± 0.59 vs 0.14 ± 0.19 nmol/L; P = .007), Igls score (good [4 of 4 cases] vs failure [3 of 4 cases] or marginal [1 of 4 cases]; P = .018) and β score (6.0 [6.0-6.0] vs 1.0 [0.0-3.5]; P = .013). SREs are prevalent among islet transplant recipients and are associated with loss of islet graft function. Timely treatment with high-dose methylprednisolone mitigates this loss. Unexplained hyperglycemia, unexpected C-peptide decrease, a predisposing event, and elevated immunologic risk are diagnostic indicators for SRE.

Evaluation of Extended Infusion Set Performance in Adults with Type 1 Diabetes: Infusion Set Survival Rate and Glycemic Outcomes from a Pivotal Trial

Background:Standard insulin infusion sets (IISs) are to be replaced every 2 to 3 days to avoid complications and diabetic ketosis due to set failure. This pivotal trial evaluated the safety and performance of a new extended-wear infusion set (EIS) when used for 7 days by adults with type 1 diabetes (T1D).Methods:This single-arm, nonrandomized trial enrolled adults (18–80 years of age) with T1D, who used their own MiniMed™ 670G system with insulin lispro or insulin aspart and the EIS for up to 7 days, across 12 consecutive wears. Safety endpoints included incidence of serious adverse events (SAEs), serious adverse device effects (SADEs), unanticipated adverse device effects (UADEs), severe hypoglycemia (SevHypo), severe hyperglycemia (SevHyper), diabetic ketoacidosis (DKA), and skin infection. The EIS failure rate due to unexplained hyperglycemia (i.e., suspected occlusion), the overall EIS survival rate, glycemic control outcomes (i.e., A1C, mean sensor glucose and time spent in established glucose ranges), total daily insulin delivered, and satisfaction with the EIS were determined.Results:The intention to treat population (n = 259, 48% men, 45.0 ± 14.1 years) wore a total of 3041 EIS devices. No SADE, UADE, or DKA events was reported. Overall rates of SAEs, SevHypo, SevHyper, and skin infection were 3.8, 2.5, 104.1, and 20.1 events per 100 participant-years. The rate of EIS failure due to unexplained hyperglycemia at the end of day 7 was 0.1% (95% confidence interval [CI]: 0.03–0.51) and 0.4% (95% CI: 0.16–1.00) for insulin lispro and aspart use, respectively. Overall EIS survival rate at the end of day 7 was 77.8% (95% CI: 76.2–79.3), glycemic control did not change, and participants reported greater satisfaction with the EIS compared with standard IISs worn before the study (P < 0.001).Conclusions:This investigation demonstrates that the EIS, when worn for up to 7 days, was safe and rated with high satisfaction, without adversely affecting glycemic control in adults with T1D.Clinical Trial Registration number: NCT04113694 (https://clinicaltrials.gov/ct2/show/NCT04113694).

100-LB: Infusion Set Survival and Performance during the Medtronic Extended-Wear Infusion Set (EWIS) Pivotal Trial

Objective: Most insulin infusion sets (ISs) are labeled for 2- or 3-days use. The Medtronic EWIS is designed to increase wear time up to 7 days. This study reports on EWIS survival and performance during the pivotal trial (ClinicalTrials.gov: NCT04113694).Method: This multi-center (15), single-arm, non-randomized, non-inferiority trial in 259 participants (18-80yrs) with T1D using the MiniMed™ 670G system (with Humalog™ or Novolog™ insulin) involved wearing a 2- or 3-day IS for 2 weeks (run-in) followed by 12 consecutive EWIS wears (study phase). The latter was worn for ≥174 hours or until set failure. Safety and performance (i.e., a priori target of <16% failure rate due to unexplained hyperglycemia) were evaluated. Exploratory analysis of glycemic control (e.g., A1C, sensor glucose and time spent at glucose ranges) and insulin use during 3-day IS and EWIS wear were also evaluated.Result: The EWIS survival rate was 74.8% versus the 67.7% rate of 2- or 3-day ISs (p<0.05). The EWIS rate was 77.8% when excluding inadvertent early removals. Glycemic control outcomes were improved during EWIS use (Table) and there were no episodes of EWIS-related severe hypoglycemia or DKA.Conclusion: The 7-day EWIS was safe and its performance was superior at ≥174 hours compared to the performance observed for 2- or 3-day infusion sets.View largeDownload slideView largeDownload slide DisclosureB. A. Buckingham: Advisory Panel; Self; Medtronic, Tolerion, Inc., Research Support; Self; Beta Bionics, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. B. Horowitz: Research Support; Self; Abbott Laboratories, BD, Celgene, Crinetics Pharmaceuticals, Gan & Lee Pharmaceuticals, Medtronic, Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes, Merck & Co., Inc., Novo Nordisk Inc. K. B. Kaiserman: Advisory Panel; Self; Medtronic, Consultant; Self; Medtronic, Employee; Self; MannKind Corporation, Research Support; Self; Medtronic, Speaker’s Bureau; Self; Medtronic, Stock/Shareholder; Self; MannKind Corporation. S. Huang: None. V. Chen: Employee; Self; Medtronic. G. Zhang: Employee; Self; Medtronic. S. Chattaraj: Employee; Self; Medtronic. J. Shin: Employee; Self; Medtronic. R. Vigersky: Employee; Self; Medtronic. R. L. Brazg: Research Support; Self; Abbott Diabetes, Ascensia Diabetes Care, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Pfizer Inc., Roche Diagnostic USA, Senseonics. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker’s Bureau; Self; BD, Medtronic, Sanofi. Y. C. Kudva: Research Support; Self; Dexcom, Inc. S. K. Garg: Advisory Panel; Self; Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Zealand Pharma A/S, Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Medtronic. G. Grunberger: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk. J. Thrasher: Advisory Panel; Self; Medtronic, Board Member; Self; Medtronic, Consultant; Self; Medtronic, Research Support; Self; Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Medtronic, Mylan N. V., Novo Nordisk, Sanofi, Speaker’s Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Medtronic, Sanofi. A. Cavale: Research Support; Self; Eli Lilly and Company, Medtronic. A. Bhargava: Research Support; Self; Abbott, AbbVie Inc., Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Boston Therapeutics, Inc., Covance Inc., Dexcom, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Insulet Corporation, Janssen Research & Development, LLC, Kowa Pharmaceuticals America, Inc., Madrigal Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Mylan N. V., Novo Nordisk, Poxel SA, Quintiles, Sanofi, Senseonics, Tolerion, Inc., Viking Therapeutics.

Characterization of hyperglycemia in patients receiving immune checkpoint inhibitors: Beyond autoimmune insulin-dependent diabetes

AimsImmune-mediated beta cell destruction is known to cause hyperglycemia in patients receiving immune checkpoint inhibitor (ICI) cancer therapy. However, it is uncommon, and little is known about the full spectrum of hyperglycemia in patients receiving ICIs. We aimed to characterize the prevalence and factors associated with hyperglycemia in patients treated with ICIs. MethodsWe retrospectively analyzed patients receiving ICIs at an NCI-designated Cancer Center. We assessed the proportion of patients with new onset hyperglycemia (random glucose >11.1 mmol/L) after starting ICIs and used logistic regression to determine hyperglycemia predictors in patients without known diabetes. ResultsOf 411 patients, 385 had post-ICI glucose data. 105 (27%) had hyperglycemia. Of this group, 29 (28%) had new onset hyperglycemia, 19 of whom had glucocorticoid-associated hyperglycemia. The remaining 10 had unexplained hyperglycemia and none had known autoimmune diabetes. Among patients without known diabetes, race/ethnicity, obesity, and pre-ICI hyperglycemia were significantly associated with hyperglycemia after starting ICIs. ConclusionsWe found that new hyperglycemia in patients receiving ICIs was most commonly related to glucocorticoids. A small patient subset had new unexplained hyperglycemia, suggesting ICIs might have a role in promoting hyperglycemia. Recognizing factors associated with hyperglycemia in this population is crucial for appropriate management.

Insulin, Not the Preservative m-cresol, Instigates Loss of Infusion Site Patency Over Extended Durations of CSII in Diabetic Swine.

Insulin infusion sets worn for more than 4-5 days have been associated with a greater risk of unexplained hyperglycemia, a phenomenon that has been hypothesized to be caused by an inflammatory response to preservatives such as m-cresol and phenol. In this cross-over study in diabetic swine, we examined the role of the preservative m-cresol in inflammation and changes in infusion site patency. Insulin pharmacokinetics (PK) and glucose pharmacodynamics (PD) were measured on delivery of a bolus of regular human insulin U-100 (U-100R), formulated with or without 2.5mg/mL m-cresol, to fasted swine following 0, 3, 5, 7, and 10 days of continuous subcutaneous insulin infusion (CSII). In a subsequent study with the same animals, biopsies were evaluated from swine wearing infusion sets infusing nothing, saline, or U-100R either with or without 2.5mg/mL m-cresol, following 3, 7, and 10 days of CSII. Exposure to m-cresol did not impact any PK or PD endpoints. PK and PD responses dropped markedly from Days 7-10, regardless of the presence of m-cresol. Histopathology results suggest an additive inflammatory response to both the infusion set and the insulin protein itself, peaking at Day 7 and remaining stable beyond.

Safety and Tolerability of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart (NovoLog) When Used in Insulin Pumps in Adults with Type 1 Diabetes: A Randomized, Open-Label Clinical Trial.

Background: The aim was to assess the safety and tolerability of the insulin aspart biosimilar/follow-on product SAR341402 (100 U/mL solution; SAR-Asp) and originator insulin aspart (100 U/mL; NN-Asp; NovoLog®) self-administered through an insulin pump.Materials and Methods: This randomized, open-label, 2 × 4-week crossover study enrolled 45 adults with type 1 diabetes (T1D). Participants were randomized 1:1 to the treatment sequence SAR-Asp/NN-Asp or NN-Asp/SAR-Asp. The basal and prandial insulin doses were individually titrated. The primary outcome was the number of participants with at least one infusion set occlusion (infusion set change due to failure-to-correct hyperglycemia [plasma glucose ≥250 mg/dL] by insulin pump bolus) during the 4-week treatment. The main secondary outcome was the number of participants with at least one episode of unexplained hyperglycemia (regardless of correction by an insulin pump bolus without apparent material defect, medical, dietary, insulin dosing reason, or pump problem).Results: The number of participants reporting ≥1 infusion set occlusion were similar between treatments: 14/43 on SAR-Asp (33 events) and 12/43 on NN-Asp (24 events). The estimated difference in infusion set occlusion risk for SAR-Asp versus NN-Asp was 4.1% (95% confidence interval: −9.3% to 17.4%). The number of participants with ≥1 episode of unexplained hyperglycemia was similar between treatments (31/43 on SAR-Asp [154 events]; 32/43 on NN-Asp [175 events]). Hypoglycemia, treatment-emergent adverse events, hypersensitivity, and injection site reactions were similar between treatments.Conclusions: SAR-Asp and NN-Asp were well tolerated and had similar infusion set occlusions over a 4-week period in insulin pump users with T1D.

997-P: Testing a Novel Infusion Set for Extended Wear Duration

This was a randomized double blinded study of a novel infusion set with and without heparin, hypothesizing that small doses of heparin would decrease thrombosis and subcutaneous inflammation. The MiniMed™ Quick-set™ infusion set was modified with a new tubing connector from current P-Cap. The P-Cap was modified to contain a foam (F) or a foam with heparin (F+H) connector. Visibly the sets appeared identical. Each participant wore two F and two F + H sets for 7 days or until set failure. The order of infusion set wear was randomly assigned. Infusion set failure was determined by unexplained hyperglycemia &amp;gt;250mg/dL with a failed correction dose, ketones &amp;gt;0.6mmol/L, evidence of infection, occlusion alarms, or adhesive failure. Infused set survival was compared to similar published 1-week studies using standard Quick-sets. There were 20 participants (mean age 29.5±8 years). Each set was worn 40 times. Length of wear and causes of failure are shown below. Length of wear was not different between the F and F+H groups, but both had improved length of wear compared to historical Quick-sets (p&amp;lt;0.05). There was no significant increase in insulin requirements or mean glucose values throughout the seven days of wear in any group. There was no difference in overall duration of wear between the F and F+H groups. Both infusion set groups intended for extended wear had significantly better survival than the historical Quick-Set™ group. Further studies are planned with the F group. Disclosure B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Medtronic. Research Support; Self; Beta Bionics, Inc., Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. T. Marcal: None. L. Hoffman: None. G. Musolino: None. L. Ekhlaspour: None. G. Zhang: None. S. Chattaraj: Employee; Self; Medtronic. Funding Medtronic Diabetes

127-LB: Longevity of the Coated ConvaTec Infusion Set with Lantern Technology

Objective: Current insulin infusion sets are approved for 2-3 days of wear; however, glucose sensors are approved for 7-14 days of wear. A commonly reported reason for discontinuing use of CGM within 1 year is not wanting to wear devices on two sites of the body. Any attempt to create a combined glucose sensor and infusion set for closed-loop control requires a set with greater longevity. The coated ConvaTec Infusion Set with Lantern Technology is a new infusion set with multiple slits and coating intended to reduce foreign body response and occlusion from bending or kinking. Methods: A pilot safety and extended wear tolerability study is being performed at Stanford University. To date, 15 adult subjects on tethered insulin pump therapy using insulin aspart or lispro have completed the study. Each participant places the set and wears it for 10 days or until set failure to establish a maximum length of infusion set wear when 80% of sets are still functional (excluding accidental “pull-outs”). Infusion set failures are based on: (1) Presence of serum ketones with hyperglycemia; (2) Unexplained hyperglycemia, unresolved with correction dose; (3) Signs of infection at the infusion site; (4) Pump occlusion alarm; and (5) Adhesive failure. Results: Two subjects did not meet failure criteria and were excluded. Of the remaining, 6 (46%) wore the novel infusion set the full 10 days and all sets lasted 7 days or more (mean 8.8 days). 3 premature set failures were associated with persistent hyperglycemia unresponsive to correction boluses on days 7-8, 3 with adhesive failure on days 7-9, and 1 with infection on day 9. Conclusions: In our previous studies assessing 353 infusion set insertions for 7 days, average length of wear was 5.1 ± 1.7 days. Thus far, the novel set has demonstrated increased longevity. The duration of wear established in this pilot study will be used to perform a masked, randomized controlled crossover study comparing the coated ConvaTec Infusion Set with Lantern Technology against standard infusion sets. Disclosure R. Lal: Consultant; Self; Abbott. P.K. Schøndorff: Employee; Self; ConvaTec Inc. L. Hsu: None. M. Heschel: Employee; Self; Unomedical a/s. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Novo Nordisk Inc., Profusa, Inc. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Beta Bionics, ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care.

137-LB: Safety Assessment of SAR341402 and NovoLog When Administered through an Insulin Pump

SAR341402 (SAR-Asp) is a biosimilar/follow-on insulin to NovoLog® (NN-Asp). This non-confirmatory, randomized, open-label, 2x4 week, 2 arm crossover study in 45 T1D patients (NCT03436498) was designed to assess the safety of SAR-Asp and NN-Asp when used in pumps (CSII) in terms of infusion set occlusions (ISO). The primary safety endpoint was to assess the number of patients with ISO using SAR-Asp and NN-Asp. ISO was defined as infusion set change due to failure to correct hyperglycemia (plasma glucose ≥250 mg/dL) by insulin bolus via the pump. The secondary safety endpoint was to assess the incidence of all cases of unexplained hyperglycemia events whether or not corrected by a bolus through the insulin pump with no apparent materials defects, medical, dietary, insulin dosing, or pump failure including infusion set occlusions as defined in the primary safety endpoint. The number of patients reporting at least one ISO was: 14/43 (32.6%) patients on SAR-Asp and 12/43 (27.9%) on NN-Asp (Table 1). The number of patients with at least one unexplained hyperglycemia was 31/43 (72.1%) on SAR-Asp and 32/43 (74.4%) on NN-Asp. The total number of unexplained hyperglycemia was 329: 154 on SAR-Asp and 175 on NN-Asp. In this study SAR-Asp and NN-Asp were well-tolerated. There was no difference in the safety profiles including ISO, hyperglycemia, hypoglycemia, hypersensitivity and injection site reactions when used in CSII. Disclosure J. Thrasher: Advisory Panel; Self; Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Senseonics. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S. Polsky: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Barbara Davis Center for Diabetes, Children’s Diabetes Foundation, Dexcom, Inc., Eli Lilly and Company, JDRF, Leona &amp; Harry Helmsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi US. L. Hovsepian: None. I.K. Nowotny: Employee; Self; Sanofi-Aventis Deutschland GmbH. Stock/Shareholder; Self; Sanofi. B. Bois De Fer: Employee; Self; IT&amp;M Stats. Stock/Shareholder; Self; IT&amp;M Stats. A. Bhargava: Consultant; Self; Sanofi-Aventis. Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Jaeb Center for Health Research, KOWA Research Institute, Inc, Medtronic MiniMed, Inc., Merck Research Laboratories, Mylan GmbH, Novo Nordisk Inc., Roche Diabetes Care, Sanofi, Theracos Sub, LLC. Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company, Sanofi-Aventis. S.K. Garg: Advisory Panel; Self; Eli Lilly and Company, Roche Pharma, Sanofi-Aventis, Zealand Pharma A/S. Research Support; Self; Eli Lilly and Company, WebMD. Funding Sanofi

Pump Users Clamor for Faster Insulin: Is Fast-Acting Insulin Aspart Ready for Them?

Recently approved in Europe, Canada, and the United States, fast-acting insulin aspart (FIASP®) is a new rapid acting insulin. Approved for subcutaneous or IV injection use, there is little data available regarding the clinical utility of FIASP in insulin pumps. The article by Zijlstra and colleagues in this issue begins to close this gap by testing pump compatibility of FIASP in the clinic. Reporting on a small (37 subjects) and short (6 weeks) study looking at aspects of infusion set propensity for clogging and malfunction, no cases of infusion set plugging in either FIASP (25 subjects) or insulin aspart (12 subjects) were seen. Unexplained hyperglycemia and premature infusion set changes were more common with FIASP than with insulin aspart. This study demonstrated sufficient safety and efficacy of FIASP in the pump setting to pave the way for longer, larger and more definitive clinical trials.

Investigation of Pump Compatibility of Fast-Acting Insulin Aspart in Subjects With Type 1 Diabetes.

Background:Ultra-fast-acting insulins, such as fast-acting insulin aspart (faster aspart), have pharmacokinetic properties that may be advantageous for patients using continuous subcutaneous insulin infusion (CSII), provided that they are compatible with and safe to use in CSII.Methods:Randomized, double-blind, parallel-group, actively controlled trial evaluating compatibility, efficacy, and safety of faster aspart in adults with type 1 diabetes using their own MiniMed Paradigm pump with Quick-Set or Silhouette infusion sets. Following run-in, subjects were randomized (2:1) to faster aspart (n = 25) or insulin aspart (n = 12) for 6 weeks. Primary endpoint was the number of microscopically confirmed episodes of infusion-set occlusions.Results:No microscopically confirmed episodes of infusion-set occlusions were observed in either arm. Seven possible infusion-set occlusions were reported by five subjects (all faster aspart); none were prompted by a plug observed by the subject (prompted by unexplained hyperglycemia [n = 6] or leakage [n = 1]) and none were confirmed. Macroscopic and microscopic evaluation showed no color change or particle/crystal formation in the infusion sets. Premature infusion-set changes were reported in 44% and 16.7% of subjects in the faster aspart and insulin aspart groups, respectively. A nonsignificant trend toward better efficacy was observed with faster aspart (estimated treatment difference [ETD] [95% CI] in HbA1c change: –0.14% [–0.40, 0.11]). No new safety issues were found in either treatment group.Conclusions:Over 6 weeks of treatment, no microscopically confirmed infusion-set occlusions were observed for faster aspart or insulin aspart, indicating similar compatibility with CSII use.

Generalized erythroderma in a neonate: Rare presentation of nosocomial candidemia with Candida tropicalis

Candida species are currently one of the most common causes of nosocomial infection in neonatal intensive care units with Candida tropicalis emerging as a frequent offending agent. Colonization precedes systemic invasive fungal infections in neonates. It generally manifests with lethargy, increased apneic episodes, feeding intolerance, late-onset thrombocytopenia, hypoglycemia, unexplained hyperglycemia, poor perfusion, and need for increased ventilator requirement. We report a 10-day-old neonate, with late-onset sepsis by C. tropicalis, presenting as generalized erythroderma. We present this case to highlight that nosocomial candidemia with C. tropicalis can present as generalized erythroderma in neonates. Maintaining adequate oral or parenteral fluidintake with monitoring of serum electrolytes is mandatory.

Insulin Infusion Set Use: European Perspectives and Recommendations.

Insulin pump users worldwide depend on insulin infusion sets (IISs) for predictable delivery of insulin to the subcutaneous tissue. Yet emerging data indicates that IISs are associated with many pump-related adverse events and may contribute to potentially life-threatening problem of unexplained hyperglycemia. The relative scarcity of published research on IISs to date, the heterogeneity of regional IIS practices, and the increasing demand for international standards guiding their use prompted convening of a panel of diabetologists and diabetes nurse educators last February, in Milan, Italy, to discuss a framework for optimizing IIS practice in Europe. The multinational panel was tasked, first, with identifying the often-overlooked IIS issues that can affect patients' experience of pump therapy—e.g., partial or complete blockage of the cannula, skin pathologies, unpredictable variations in insulin absorption, dislodgment, and the demands of site rotation and set changes—and, second, with establishing direction for developing cohesive protocols to assure long-term success.As reported in this article, the panel examined IIS-related complications of pump therapy encountered in clinical practice, considered country-wide policies to prevent and mitigate such complications, and updated priorities for improving IIS education on issues of device selection, skin care, and troubleshooting unexplained hyperglycemia. These recommendations may be more relevant with the possibility of closed-loop systems available in the near future.

Improving Patient Experience With Insulin Infusion Sets: Practical Guidelines and Future Directions.

Insulin infusion sets (IISs) are an essential component of safe and effective insulin pump therapy. Establishing best practices for their use has been impeded by a lack of formal study and limited resources for clinician and patient education. Recent innovations in IIS science promise to change this status quo by increasing awareness of such problems as unexplained hyperglycemia and infusion set occlusion. In August 2015, a panel of diabetologists and certified diabetes educators from various disciplines was convened to reconsider IIS-related complications of pump therapy, to better characterize infusion set factors affecting patient experience, and to update priorities for optimizing current technologies. Actionable guidelines were provided for addressing common issues, including skin reactions, site rotation and set changes, dislodgment of the infusion set, and partial or complete blockage of the catheter. These issues may underlie episodes of IIS failure and/or unexplained hyperglycemia. Development of practical tools and standardized guidelines for empowering patients to prevent, diagnose, and troubleshoot IIS problems that contribute to unexplained hyperglycemia will be necessary to realize the full benefit of insulin pump therapy along the continuum of diabetes education.

Letter Written in Response to van Bon et al.: “Insulin Glulisine Compared to Insulin Aspart and to Insulin Lispro Administered by Continuous Subcutaneous Insulin Infusion in Patients with Type 1 Diabetes: A Randomized Controlled Trial”

Dear Editor: Further data regarding the use of specific insulins for continuous subcutaneous insulin infusion (CSII) are always of interest because of the relative paucity of research in this area. As such, the recent article by van Bon et al.1 is of particular value. However, we consider that some of the conclusions, as presented by the authors, deserve greater scrutiny. First, according to the methods, this was a randomized, controlled, open-label, crossover clinical trial designed to show the superiority of insulin glulisine over both insulin aspart and insulin lispro. For the primary outcome (unexplained hyperglycemia and/or perceived perfusion set occlusion), a numerically greater percentage of patients reported this outcome with glulisine (68.4%) compared with either aspart (62.1%) or lispro (67.3%). The authors refer to a lack of statistical significance (P=0.04 for glulisine vs. aspart, P=0.03 for glulisine vs. lispro) for this outcome, implying little to no difference among the three insulins, rather than as a failure to show superiority (which was what the study was powered to detect). Furthermore, there were significant differences among the three insulins in the secondary outcomes of monthly rate of unexplained hyperglycemia or perceived infusion set occlusion, rate of significant hyperketonemia and/or hyperketonemia at risk of ketosis, and rate of symptomatic and nocturnal hypoglycemia. These results seem to belie the conclusions of the authors that there were no significant differences among the three insulins when used in CSII. I would also question the authors' suggestions that a trend toward greater occurrence of unexplained hyperglycemia and perceived infusion set occlusion seen in this study with insulin glulisine compared with insulin aspart and lispro should be taken as balancing the results from the previous study by Hoogma and Schumicki2 in which the opposite trend was seen. As the previous study was not statistically powered to detect superiority for this outcome, whereas the study by van Bon et al.1 was explicitly designed to do so, these results should instead override the previous findings. Second, the article describes various post hoc analyses that were carried out on the final data set but that had not previously been planned or described in the study design. There appears to be no well-defined reason for these additional statistical analyses, and I would query their relevance and utility. The relative value of any results produced by such analyses must be considered of lesser weight than the main study as cohort numbers were not chosen with these in mind, and thus the statistical power may not be sufficient to show a true difference. Third, the authors place a large amount of emphasis on the results relating to time to change infusion set, stressing the point that less difference was seen in occurrence of occlusion between glulisine and aspart or lispro when sets were changed more frequently. This finding is of questionable clinical relevance when compared with the observation that the timings seen in this study, with patients changing catheters much less frequently than advised, are much more likely to be applicable to a real-world scenario than a rigidly enforced limit of every 2 days. Following the results of this study, it seems that patients using glulisine in infusion sets should be instructed to change their infusion sets every 2 days. This requirement for more frequent changes could be due to a lower chemical and physical stability of glulisine compared with lispro and aspart, presenting challenges in the pump setting. Finally, the authors suggest that the increased frequency of hypoglycemia seen with glulisine could be the result of slight overdosing of glulisine throughout this study. They refer to previous studies in which patients have required a lower basal dose of glulisine than other insulins. In this current study, although initial dosage was based on the patient's dose at trial commencement, dosing adjustments for each of the study insulins were based on each patient's glucose control in line with recommendations from the American Diabetes Association. If the glulisine dose was high enough to lead to increased hypoglycemic events, it could be expected that average glycosylated hemoglobin levels in these patients would be decreased compared with aspart and lispro. Throughout the study, glycemic control remained stable across all three treatment groups with no differences observed between glulisine and aspart or glulisine and lispro. Instead of stating in the conclusion that “all three short-acting insulin analogs could be used in CSII as no difference was seen among GLU, ASP, and LIS on the primary outcome measure..,” the authors should have reported that glulisine failed to show superiority over either aspart or lispro, countering the trend seen in the previous trial of Hoogma and Schumicki,2 and was inferior with regard to several of the outcomes investigated.

Insulin Glulisine Compared to Insulin Aspart and to Insulin Lispro Administered by Continuous Subcutaneous Insulin Infusion in Patients with Type 1 Diabetes: A Randomized Controlled Trial

In a previous pilot study comparing insulin glulisine (GLU) with insulin aspart (ASP) administered by continuous subcutaneous insulin infusion (CSII), GLU-treated patients did show a trend toward fewer catheter occlusions compared with ASP-treated patients. Here we performed a randomized open-label, three-way crossover, controlled multicenter study comparing GLU with ASP and insulin lispro (LIS). Subjects with type 1 diabetes were allocated to one of three treatment orders-GLU-ASP-LIS, ASP-LIS-GLU, or LIS-GLU-ASP-with each insulin used for 13 weeks. The study was designed to demonstrate the superiority of GLU over ASP and LIS on unexplained hyperglycemia and/or perceived infusion set occlusion. A prespecified P value of 0.025 was considered significant to correct for multiple testing. Percentages of subjects with at least one unexplained hyperglycemia and/or infusion set occlusion were not significantly different between GLU and ASP (68.4% [62.7-74.1%] vs. 62.1% [56.2-68.1%], P = 0.04) and GLU and LIS (68.4% [62.7-74.1%] vs. 61.3% [55.4-67.3%], P = 0.03). No differences were seen in hemoglobin A1c at end point, most points of the seven-point glucose curves, severe hypoglycemia, and symptomatic ketoacidosis. The overall rate of hypoglycemia with a plasma glucose level below 70 mg/dL per patient-year was significantly different between GLU and ASP (73.84 vs. 65.01, P = 0.008) and GLU and LIS (73.84 vs. 62.69, P < 0.001). Insulin doses remained unchanged during the trial. GLU was not superior to ASP and LIS with no significant difference seen among GLU, ASP, and LIS in CSII use with respect to unexplained hyperglycemia and/or perceived catheter set occlusion. GLU was associated with a higher frequency of symptomatic hypoglycemia, possibly because of slight overdosing, as previous trials suggested lower insulin requirements when GLU is initiated in type 1 diabetes.